PTPase

Intracellular and extracellular ROS activate tyrosine and serine-threonine kinases (i.e., the MAPK family members). Following TNF-a, TGF-f5 or EGF stimulation, intracellular ROS are generated which stimulate various signaling pathways [73], Tyrosine kinase receptors (e.g., EGF, PDGF and TGF-a) may be activated by ROS directly via protein sulfhydryl group modifications, or inhibition of phosphotyrosine phosphatases (PTPases) and subsequent receptor activation. The latter is possible as PTPases contain a redox-sensitive cysteine at their active site [78], and oxidation of protein sulfhydryl groups results in the inactivation of PTPases. 

An interesting facet of the molecular modelling studies [66] was that they suggested that one methyl group of the hydroxylamine ligand was in an orientation suitable for replacement by other functionality. This is potentially important because PTPase active site residues are highly conserved, and enzyme selectivity is conferred... 

Workers at Ontogen [82,83] reported the use of the OntoBLOCK system which utilizes a Tecan robot. They have implemented this technology for solid-phase synthesis to generate over 50 000 compounds corresponding to libraries of pyrroles, phosphonates, phosphinates, lactams, imidazoles, hydantoin imides and thioimides, oxazoles, and b-lac-tams. These libraries have resulted in potent and selective inhibitors of iNOS, PTPases and cdc25 phosphatase and compounds that reverse the P-glycoprotein (Pgp)-based multiple drug resistance (MDR) phenomenon in cellular assays and in animal models [98],... 

PTPases, P-Tyr phosphatases PUVA therapy, psoralen with ultraviolet A light therapy PYK, pyruvate kinase... 

PTEN, phosphatase and tensin homolog PTPase, phosphotyrosine phosphatase PYY, peptide YY... 

Figure 1. Schematic view of the active site in a typical PTPase.

---